The objective of this project is to advance understanding of the mechanisms that underlie normal and abnormal puberty, and to apply this knowledge to improve existing therapy for disorders of puberty. Since somatic growth is a major determinant of the timing of pubertal onset, a further objective is to clarify the mechanisms of normal growth and of growth failure. Principal areas of clinical investigation include the mechanism of premature thelarche and of the gonadotropin-independent forms of precocious puberty, the developmental changes in hypothalamic regulation of gonadotropin secretion, the behavioral changes associated with normal and abnormal pubertal development, the mechanisms of prepubertal and pubertal growth, the role of pubertal sex steroids in the acquisition of normal adult bone density, the treatment of central precocious puberty with an analog of luteinizing hormone-releasing hormone, the treatment of familial male isosexual precocious puberty with combined antiandrogen and aromatase inhibitor, the evaluation of new approaches to the diagnosis of growth hormone deficiency and to the differential diagnosis of delayed puberty, the treatment with synthetic parathyroid hormone of children with hypoparathyroidism, the treatment with growth hormone of children with Turner syndrome and with non-growth hormone-deficient short stature, and the treatment with insulin-like growth factor-1 of children with Laron short stature and of children with idiopathic short stature. The principal areas of laboratory investigation include the structure and function of the regulatory sequences of the human gonadotropin-releasing hormone (GnRH) gene, the structure of the human GnRH gene in families with GnRH-dependent precocious puberty or with idiopathic hypogonadotropic hypogonadism, linkage analysis of the gene for familial male precocious puberty to the luteinizing hormone receptor or other loci, and hormonal regulation of epiphyseal transforming growth factor-beta, fibroblast growth factor, and platelet-derived growth factor. To examine the effects of these growth factors in vivo we are studying rabbits bearing small needles implanted into the proximal tibial epiphyses and connected to osmotic minipumps.